SUMMARY/ABSTRACT This application is in response to PAR-17-054, which calls for combining multiple existing cohorts in order to improve statistical power and clarify risk and protective factors for Alzheimer?s disease and related dementias (AD/ADRD). While it is well-recognized that ADRD occurrence reflects the influences of multiple genes and multiple environmental and lifestyle risk and protective factors, designs to elucidate potentially informative gene-environment interplay have been rarer. Consequently we propose to employ a large consortium of longitudinal twin studies of adult development and aging, with measures of risk and protective factors across different life stages, to address key questions about etiological mechanisms in ADRD. By effectively treating one twin as the control for the other, we will test for risk or protection associated with lifestyle, health, and psychosocial factors while controlling for genetic factors, thereby strengthening causal inferences from observational studies. We will also use twin designs to test the extent to which the association between risk or protective factor and ADRD reflects shared genetic or shared environmental explanations. In addition to within-pair and quantitative twin models, we will use polygenic risk scores (PRS) as indicators of individual genetic risk for ADRD to test whether genetic risk for ADRD alters susceptibility to other risk and protective factors, and PRS for specific risk and protective factors to test whether genetic risk for these factors alter their association with ADRD. We especially focus on clarifying the nature of the relationship between education and ADRD; midlife obesity, vascular risk, depression, and physical activity; and sex or gender differences in genetic risk, exposure to specific risk factors, susceptibility to specific risk factors, and sex differences in genetic interactions with specific risk factors. These questions importantly inform the design of interventions to prevent or slow occurrence of dementia. The consortium on Interplay of Genes and Environments across Multiple Studies (IGEMS) includes eight twin registries in the U.S., Sweden, Denmark, Finland, and Australia. IGEMS brings nearly 50,000 individual twins, with over 5000 identical twin pairs for within-pair difference models, nearly 7000 same-sex fraternal twin pairs, and over 3000 opposite sex pairs for sex difference models. Outcomes include: clinically diagnosed dementia; dementia diagnoses obtained by linkage to national health registries; psychometrically determined MCI; scores on a latent dementia indicator based on cognitive and functional evaluations. A large subset of IGEMS participants has genome wide genotyping from which we have computed PRS. For analyses of risk and protective factors, mediators, and covariates, we have data from surveys collected in midlife as well as later and from linkages to administrative data, e.g., conscription records and health registries. Already harmonized measures include: education, occupation, cognitive tests, BMI, depression, anxiety.